title: Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells.
abstract: Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPARgamma induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H(2)O(2) levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulin-resistant cells, suggesting that GPx3 is required for the regulation of PPARgamma-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPARgamma is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Chung
authors.forename: Min
authors.initials: M
authors.lastname: Kim
authors.forename: Byoung-Soo
authors.initials: BS
authors.lastname: Youn
authors.forename: Nam Seok
authors.initials: NS
authors.lastname: Lee
authors.forename: Ji Woo
authors.initials: JW
authors.lastname: Park
authors.forename: In Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Yun Sok
authors.initials: YS
authors.lastname: Lee
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
authors.forename: Young Min
authors.initials: YM
authors.lastname: Cho
authors.forename: Hong Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D003920:Diabetes Mellitus / Q000201:enzymology; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000187:drug effects / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000201:enzymology*; D047495:PPAR gamma / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D006861:Hydrogen Peroxide; C486484:GPX3 protein, human; D005979:Glutathione Peroxidase; D005947:Glucose